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9136 Background: Lung cancer organoids (LCOs) were expected to be the potential precision medicine approach for clinical response prediction. However, the clinical applications of both tissue and malignant serous effusions (MSE) derived LCOs were rarely reported. Our previous work demonstrated that MSE-derived LCOs maintain the genomic signature of the original tumor. In this study, we aimed to create LCOs using tissue or MSE, then validate the reliability of the model by comparing LCOs and their origin from the pathological and molecular levels. Furthermore, drug sensitivity tests of LCOs were also performed to evaluate the feasibility of LCO drug test as an approach for personalized medicine. Methods: Primary or metastatic tumor tissues were obtained from advanced lung cancer patients through core biopsy or surgically resected biopsy at the Guangdong Provincial People’s Hospital. MSEs were also collected. LCOs were generated from the obtained tissue and MSE, and the pathological features and genomic profiles were verified by analyzing the consistency with their origin. Then, the drug sensitivity scheme was formulated to follow the principles of clinical medication. In addition, proteomics analysis by 4D LC-MS/MS was also performed to analysis the molecular details of combinational therapy. Results: In our study, we generated 213 LCOs from 106 patients, mainly from MSE. The success rate to generate LCOs derived from MSE was 81.4% (131/161). The concordance rate of pathological phenotypes of LCOs samples verified by immunohistochemistry with clinical samples was 75% (63/84). In our cohort, LCO based drug sensitivity tests (LCO-DST) of targeted therapies were performed to predict the tumor response, and the AUC value of ROC analysis of osimertinib in EGFR-mutant adenocarcinoma reached 0.94(LCOs samples = 15, p= 0.0047). There were 2 patients with advanced lung adenocarcinoma, one with de novo EGFR mutation /MET amplification and the other with EGFR mutation combined with acquired RET fusion. The results of LCO based drug tests of 2 patients showed that combined targeted therapy (osimertinib plus savolitinib/cabozantinib) showed high tumor inhibition rate validated in clinical treatment and made differences. Then, 4D label-free high through-put proteomic analysis was performed in the patient with EGFR mutation and acquired RET fusion, demonstrating caspase 3 increased dramatically in combination of osimertinib and BLU-667 and the downstream proteins of EGFR and RET were down-regulated. Conclusions: LCOs derived from MSE faithfully reflected the pathological and genomic features of their original patients. The LCOs based drug test results are remarkably consistent with the tumor response. These results suggested the important prospects of LCO as an in vitro model for lung cancer precision medicine.

e21021 Background: BRAF variants were reported resistant mechanisms to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC). However, concomitant somatic variations other than BRAF variants and efficacy of subsequent treatment remained unclear. Methods: From October 2016 to May 2020, advanced NSCLC patients who underwent next-generation sequencing and were detected with co-mutation of BRAF and EGFR activating mutations are retrospectively included. Since June 2020, EGFR-mutant patients with acquired BRAF V600E after progression from previous Osimertinib are prospectively arranged to explore efficacy of the EGFR-BRAF co-inhibition. Results: Fifty-eight patients were retrospectively identified and five patients were prospectively included. BRAF variants was acquired after a median time of 22.7 months from initial diagnosis. Variations of TP53, PIK3CA, RB1, MET, LRP1B, APC, CDKN2A, MYC, ERBB2 and SMAD4 were over 10%, which were enriched in cell cycle/p53 pathway, EGFR downstream and bypass pathway. Subsequently, median progression-free survival was 5.0 months for chemotherapy and 2.1 months for TKI treatment without targeting both EGFR and BRAF respectively (p = 0.019). Osimertinib plus vemurafenib (n = 4) or dabrafenib + trametinib (n = 1) was prospectively administrated in five patients. Median PFS was 7.8 months. Grade 3 rash was observed in one patient. Upon disease progression, activation of RAS signaling was observed. Conclusions: Variations of EGFR downstream or bypass pathway were also frequent in patient with co-mutation of EGFR and BRAF. Efficacy of subsequent TKI without targeting both EGFR and BRAF was inferior to chemotherapy. EGFR-BRAF co-inhibition showed improved efficacy. More treatment strategy should be explored in the future.

9032 Background: Immunotherapy has become standard therapy for untreated advanced NSCLC. However, no direct comparison between anti-PD-1 inhibitors has been reported. Methods: CTONG1901 is an open label, randomized, phase II clinical trial to compare sintilimab and pembrolizumab in monotherapy or combination with chemotherapy for advanced NSCLC at first-line setting. The primary endpoint was objective response rate (ORR). Patient without EGFR and ALK alteration were enrolled. Patients with PD-L1 tumor proportion score (TPS) ≥50% were randomly to receive sintilimab (A) or pembrolizumab (B) ; and with TPSst stage. When ≥4 patients achieve partial response (PR) in sintilimab arms, the study will enter into 2nd stage and the sample size will be calculated based on the ORR results of the 1st stage. Results: The ORR was 57.1% in sintilimab and 33.3% in pembrolizumab arms at the 1st stage. The study successfully entered into the 2nd stage. 48 additional patients should be enrolled after calculation. When 15 PR in sintilimab arms achieved, the primary endpoint will be reached. From Mar. 2020 to Jan. 2022, 71 patients were screened and 68 patients were enrolled in two stages. Histologic subtypes and brain metastasis were well balanced between arms. As of Dec. 31st 2021, the median follow-up was 5.6 months. The confirmed ORR was 45.5% (15/33) in sintilimab vs. 28.6% (10/35) in pembrolizumab arms (A vs. B: 30.8% [4/13] vs. 28.6% [4/14]; C vs. D: 55.0% [11/20] vs. 28.6% [6/21]). Unconfirmed ORR was 57.6% vs. 42.9% and disease control rate (DCR) was 87.9% vs. 91.4% in sintilimab and pembrolizumab arms. The primary endpoint was reached. Survival data was immature. Any grade and 3-4 grade treatment-related adverse events (TRAEs) were comparable in sintilimab and pembrolizumab arms (Table). Conclusions: This is the first head-to-head phase II study to directly compare two anti-PD-1 antibodies as first-line treatment in advanced NSCLC. The result suggested comparable tumor response and similar safety profile between sintilimab and pembrolizumab. Clinical trial information: NCT04252365. [Table: see text]

8578 Background: IMpower133 showed benefits in both progression-free survival (PFS) and overall survival (OS) of etoposide/carboplatin plus atezolizumab (ECT) regimen in extensive-stage small-cell lung cancer (ES-SCLC), but the absolute benefit was limited. Previous studies have classified SCLC patients by RNA-seq clustering analysis to explore the dominant population for treatment, but was difficult for clinical application. We aimed to explore whether expressive status of Yes-Associated Protein 1 (YAP-1) can screen dominant population of immunotherapy among ES-SCLC patients. Methods: We selected ES-SCLC patients treated in our hospital from Jan, 2018 to Jul, 2021, and enrolled 21 patients with ES-SCLC received ECT regimen whose formaldehyde-fixed, paraffin-embedded sample was reachable. Assessments of complete remission (CR), partial remission (PR), disease stable (SD) and progressive disease (PD) were according to the efficacy evaluation criteria of solid tumor (RECIST) version 1.1. Immunohistochemistry (IHC) of YAP-1 (ET1608-30, 1/100) was conducted. The H-score was calculated by IHC Profiler. All statistical analyses were evaluated using SPSS 22.0, X-tile 3.6.1, and Excel. P values < 0.05 were considered statistically significant. Results: Baseline information was provided in table. The median H-score of responders (CR/PR patients) and non-responders were 13.97 (95%CI: 8.97-16.30) and 23.72 (95%CI: 8.13-75.40) that were significantly different (P＜0.05). H-score and PFS showed negative correlation by spearman (r = -0.603). Patients were divided into two groups as low expression group (H-score ≤25.00, n = 16) and high expression group (H-score ＞25.00, n = 5) according to the cut-off value of H-score. The median PFS of these two groups were 7.1m (95%CI: 2.6-11.6m) and 3.4m (95%CI: 0.9-5.9m), respectively. K-M curves of PFS were significantly different (P＜0.05). Conclusions: Our preliminary results have indicated a potential efficacy predictive value of YAP-1 protein. And the expression level of YAP-1 protein was negatively correlated with efficacy of ECT in ES-SCLC patients. [Table: see text]